Oligogenic heterozygous inheritance of sperm abnormalities in mouse
- CHU Grenoble-Alpes, France
- INSERM, CNRS, University Grenoble-Alpes, France
- University of Geneva Medical School, Switzerland
Abstract
Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects - the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.
Data availability
Figure 5 - Source Data 1, Figure 6 - Source Data 1 and Figure 7 - Source Data 1 contain the numerical data used to generate the figures.
Article and author information
Author details
Guillaume Martinez
Christophe Arnoult
Funding
Agence Nationale de la Recherche (ANR-19-CE17-0014)
- Pierre F Ray
- Christophe Arnoult
Agence Nationale de la Recherche (ANR-21-CE17-0007)
- Guillaume Martinez
- Charles Coutton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures were conducted according to a protocol approved by the local Ethics Committee (ComEth Grenoble No. 318), by the French government (ministry agreement number #7128 UHTA-U1209-CA), and by the Direction Générale de la Santé (DGS) for the State of Geneva.
Reviewing Editor
- Jean-Ju Chung, Yale University, United States
Publication history
- Received: November 8, 2021
- Preprint posted: November 16, 2021 (view preprint)
- Accepted: April 7, 2022
- Accepted Manuscript published: April 22, 2022 (version 1)
- Version of Record published: May 5, 2022 (version 2)
Copyright
© 2022, Martinez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Oligogenic heterozygous inheritance of sperm abnormalities in mouse
eLife 11:e75373.
https://doi.org/10.7554/eLife.75373
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